Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is more or less completely lost. About 2% of all people suffer from diabetes.
Since the discovery of insulin in the 1920's, continuous strides have been made to improve the treatment of diabetes mellitus. To help avoid extreme glucose levels, diabetic patients often practice insulin replacement therapy, whereby insulin is administered by injection.
In the treatment of diabetes mellitus, many varieties of insulin compositions have been suggested and used, including regular insulin, Semilente® insulin, isophane insulin, insulin zinc suspensions, protamine zinc insulin, and Ultralente® insulin. As diabetic patients typically are treated with insulin for several decades, there is a major need for safe and life quality improving insulin compositions. Some of the commercially available insulin compositions are characterized by a fast onset of action, while other compositions have a relatively slow onset but show a more or less prolonged action. Fast acting insulin compositions are usually solutions of insulin, while retarded acting insulin compositions can be suspensions containing insulin in crystalline and/or amorphous form precipitated by addition of zinc salts alone or by addition of protamine or by a combination of both. In addition, some patients use compositions having both a fast onset of action and a more prolonged action. Such a composition may be an insulin solution wherein protamine insulin crystals are suspended. Some patients prepare the final composition themselves by mixing an insulin solution with a suspension composition in the desired ratio.
Human insulin consists of two polypeptide chains, the so-called A and B chains, which contain 21 and 30 amino acid residues, respectively. The A and B chains are interconnected by two cystine disulphide bridges and a third disulfide bridge is intra A chain. Insulin from most other species has a similar construction, but may not contain the same amino acid residues at corresponding positions.
The development of genetic engineering has made it possible to easily prepare a great variety of insulin compounds analogous to human insulin. In these insulin analogs, one or more of the amino acid residues have been substituted with other amino acid residues which can be coded for by the nucleotide sequences. Since human insulin, as explained above, contains 51 amino acid residues, it is obvious that a large number of insulin analogs is possible, and a great variety of analogs with interesting properties have been prepared. In human insulin solutions with a concentration of interest for injectable compositions, the insulin molecule is present in associated form as a hexamer (Brange et al. Diabetes Care 13, (1990), 923-954). After subcutaneous injection, it is believed that the rate of absorption by the blood stream is dependent on the size of the molecule, and it has been found that insulin analogues with amino acid residue substitutions which counteract or inhibit this hexamer formation have an unusually fast onset of action (Brange et al.: Ibid). This can be of great therapeutic value for the diabetic patient.
A general survey of pharmaceutical compositions containing insulin is given by Brange et al. in Galenics of Insulin, Springer-Verlag (Berlin, 1987). Scott and Fisher (1936) disclose suspensions of insulin containing 1 mM protamine sulphate and 0.15 mM insulin at pH 7.2.
Pharmaceutical compositions which are based on analogues of human insulin have e.g. been presented by Heinemann et al., Lutterman et al. and Wiefels et al. at the “Frontiers in Insulin Pharmacology” International Symposium in Hamburg, 1992.
U.S. Pat. No. 5,474,978 (Eli Lilly) discloses a rapidly acting parenteral formulation comprising a human insulin analogue hexamer complex consisting of six monomeric insulin analogues, zinc ions and at least three molecules of a phenolic derivative.
Normally, insulin compositions are administered by subcutaneous injection. What is important for the patient is the profile of action of the insulin composition, i.e. the action of insulin on the glucose metabolism as a function of the time from the injection, including the time for the onset of insulin action, the maximum value and the total duration of action. A variety of insulin compositions with different profiles of action are required by patients. An individual patient may thus on the same day use insulin compositions with very different profiles of action. The profile of action required for any given patient at any given time depends upon several factors, e.g. the time of the day and the amount and composition of any meal eaten by the patient.
Also important for the patient is the chemical stability of the insulin compositions, especially due to the abundant use of pen-like injection devices such as devices which contain Penfill® cartridges, in which an insulin composition is stored until the entire cartridge is empty. This may last 1 to 2 weeks or more for devices containing a 1.5 or 3.0 ml cartridge. During storage, covalent chemical changes in the insulin structure occur. This may lead to the formation of molecules which are less active and potentially immunogenic such as deamidation products and higher molecular weight transformation products (dimers, polymers, etc.). A comprehensive study on the chemical stability of insulin is given by Jens Brange in “Stability of Insulin”, Kluwer Academic Publishers, 1994.
Compositions comprising insulin and insulin analogues are traditionally formulated using various additives, for example sodium phosphate (buffer), Zn2+ (stabilizer), phenol/m-cresol (preservative and stabilizer), sodium chloride (isotonicity agent and stabilizer), and glycerol/mannitol (isotonicity agents).
The shelf-life of insulin products is mainly compromised by the formation of soluble aggregates (dimers and polymers) over time, despite the fact that insulin is typically stored at a low temperature of no more than about 5° C., which improves the shelf-life considerably compared to storage e.g. at room temperature. In addition, insulin products are subject to the formation of insoluble aggregates (fibrils) as a result of shaking, e.g. when carried in the pocket of a patient or during transport. It is essential for the quality of an insulin product that the tendency to form such soluble and insoluble aggregates as a result of chemical or physical influences is reduced to an absolute minimum.
Acta Pharmaceutica Nordica 4(4), 1992, pp. 149-158 discloses insulin compositions with a sodium chloride concentration in the range of 0 to 250 mM. The major part of the compositions, including those which additionally comprise glycerol, contain a rather high amount of sodium chloride, i.e. 0.7%, corresponding approximately to a concentration of 120 mM.
U.S. Pat. No. 5,866,538 (Novo Nordisk) discloses insulin compositions having improved chemical stability, the compositions comprising human insulin or an analog or derivative thereof, glycerol and/or mannitol and 5-100 mM of a halogenide, e.g. sodium chloride.
U.S. Pat. No. 6,174,856 (Novo Nordisk) discloses stabilized aqueous compositions comprising human insulin or an analog or derivative thereof, a buffer selected from glycylglycine, citrate or TRIS and metal ions, in particular, calcium or magnesium ions.
U.S. Pat. No. 6,451,762 (Novo Nordisk) discloses protracted acting water soluble aggregates of derivatives of human insulin.
U.S. Pat. No. 6,551,992 (Eli Lilly) discloses monomeric insulin analog formulations stabilized against aggregation in which the buffering agent is either TRIS or arginine.
U.S. Pat. No. 5,747,642 (Eli Lilly) discloses parenteral pharmaceutical formulations which comprise a monomeric insulin analog, zinc, protamine and a phenolic derivative.
U.S. Pat. No. 6,465,426 (Eli Lilly) discloses insoluble compositions comprising an acylated insulin or acyalted insulin analog complexed with zinc, protamine and a phenolic compound such that the resulting microcrystal is analogous to the neutral protamine Hagedorn (NPH) insulin crystal form.
Although progress has been made in the chemical and physical stabilization of insulin-containing compositions, the need still remains for soluble, stable formulations of insulin or analogs or derivatives thereof, or mixtures of the foregoing, that exhibit a prolonged action profile upon administration in vivo.